The role of Ezrin in hepatocytes in the onset of excretory liver failure
in: Infection (2019)
Introduction: Ezrin and Radixin belong to the ERM protein family and share a high sequence homology. ERM proteins couple the cytoskeleton to integral plasma membrane proteins and thereby contribute to the shaping of membrane structures. In hepatocytes, ERM proteins bind to bile acid transporters such as MRP2 and are involved in the formation of the canalicular brush border. Loss or inactivation of ERM proteins causes an intracellular redistribution of MRP2 and other canalicular transporters and results in loss of the canalicular brush border, leading to cholestasis. In sepsis, the often occurring liver dysfunction shows a similar distribution, with loss of the brush borders and disturbed distribution of MRP2. Cellular mechanisms leading to cholestasis are only partly understood. Objectives: While Radixin function in the liver is well characterized, the function of Ezrin in hepatocytes remains unclear also due to the lethality of the (global) Ezrin knock-out mice. Chai et al.  recently proposed that Ezrin promotes cholestasis in human hepatocytes, by actively contributing to the removal of MRP2 from the canalicular membrane of hepatocytes. Methods: We generated hepatocyte-specific Ezrin knock-out mice to investigate the relevance of Ezrin in hepatocytes. Using bile duct ligation to induce cholestasis the pathophysiological role suggested by Chai et al.  was studied. The morphological and functional changes are studied by immunostaining (MRP2), electron microscopy and spectroscopy. Results: Ezrin KO mice showed no histological liver damage, liver dysfunction or disturbed brush border formation under physiological conditions. Cholestasis did not induce a phenotype in the liverspecific Ezrin knock-out mice. Conclusions: Ezrin neither plays a role in the development and physiological function of hepatocytes nor in the pathophysiology of cholestasis. Therefore Radixin is confirmed as the major and functional relevant ERM protein responsible for upholding the canalicular membrane structure and the MRP2 localization in hepatocytes. Reference:  Chai et al. Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis, J Hepatol. (2015), 63(6): 1440–1448.